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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 1 432-440
Copyright © 2000 by The Endocrine Society

Original Studies

Mechanisms of Coxsackievirus-Induced Damage to Human Pancreatic ß-Cells1

Merja Roivainen, Suvi Rasilainen, Petri Ylipaasto, Riikka Nissinen, Jarkko Ustinov, Luc Bouwens, Décio L. Eizirik, Tapani Hovi and Timo Otonkoski2

Enterovirus Laboratory, National Public Health Institute (M.R., P.Y., R.N., T.H.), FIN-00300 Helsinki, Transplantation Laboratory, Haartman Institute (S.R., J.U., T.O.), and Hospital for Children and Adolescents (T.O.), University of Helsinki, FIN-00014 Helsinki, Finland; and the Diabetes Research Center, Vrije Universiteit Brussel (L.B., D.L.E.), B-1090 Brussels, Belgium

Address all correspondence and requests for reprints to: Dr. Merja Roivainen, Enterovirus Laboratory, National Public Health Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland. E-mail: merja.roivainen{at}ktl.fi

Enteroviruses may be involved in the pathogenesis of insulin-dependent diabetes mellitus, either through direct ß-cell infection or as triggers of autoimmunity. In the present study we investigated the patterns of infection in adult human islet cell preparations (consisting of 56 ± 14% ß-cells) by several coxsackieviruses. The cells were infected with prototype strains of coxsackievirus B (CBV) 3, 4, and 5 as well as coxsackievirus A9 (CAV-9). The previously characterized diabetogenic strain of coxsackievirus B4 (CBV-4-E2) was used as a reference. All viruses replicated well in ß-cells, but only CBVs caused cell death. One week after infection, the insulin response of the ß-cells to glucose or glucose plus theophyline was most severely impaired by CBV-3 and CBV-5 infections. CBV-4 also caused significant functional impairment, whereas CAV-9-infected cells responded like uninfected controls. After 2 days of infection, about 40% of CBV-5-infected cells had undergone morphological changes characteristic of pyknosis, i.e. highly distorted nuclei with condensed but intact chromatin. Both mitochondria and plasma membrane were intact in these cells. DNA fragmentation was found in 5.9 ± 1.1% of CBV-5-infected ß-cell nuclei (2.1 ± 0.3% in controls; P < 0.01). CAV-9 infection did not induce DNA fragmentation. One week after infection the majority of infected cells showed characteristics of secondary necrosis. Medium nitrite and inducible nitric oxide synthase messenger ribonucleic acid levels were not significantly up-regulated by CBV infection. These results suggest that several enteroviruses may infect human ß-cells. The infection may result in functional impairment or death of the ß-cell or may have no apparent immediate adverse effects, as shown here for CAV-9. Coxsackie B viruses cause functional impairment and ß-cell death characterized by nuclear pyknosis. Apoptosis appears to play a minor role during a productive CBV infection in ß-cells.




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